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“Sessioneplenaria:cronicitàeterapieinnovative”
Catania, 24 ottobre 2015
Impatto terapeutico, economico ed organizzativo dei nuovi farmaci per la
sclerosi multipla
Luigi M.E. Grimaldi
0,09% 0,71% 0,96% 1%
6,7%
12,1%
0
5
10
15
MS Epilepsy PD+HD Stroke AD Migraine
MS = multiple sclerosis; PD+HD = Parkinson disease + Huntington disease; AD = Alzheimer’s disease.1. Hirtz D. et al. Neurology. 2007;68:326–337. 2. National Institute of Neurological Disorders and Stroke. Available at: www.ninds.nih.gov. Accessed May 17, 2007.
Dis
ease
pre
vale
nce,
%Prevalenza delle
malattie neurologiche
Costi sanitari diretti annuali per paziente Costo sanitario diretto
Costo medicinale
Costo sanitario
Costo recidive
Inizializzazione
fingolimod € 21.004 € 20.272 € 680 € 52 € 570
natalizumab € 23.476 € 22.185 € 1281 € 10
IFN beta 1A (Avonex) € 10.291 € 9.864 € 323 € 104
IFN beta 1A (Rebif 22) € 10.706 € 10.279 € 323 € 104
IFN beta 1A (Rebif 44) € 14.248 € 13.821 € 323 € 104
IFN beta 1b (Betaferon) € 6.327 € 5.900 € 323 € 104
IFN beta 1B (Extavia) € 6.327 € 5.900 € 323 € 104
glatiramer acetato € 9.949 € 9.522 € 323 € 104
teriflunomide € 10.406 € 9.947 € 355 € 104
dimetil fumarato € 12.646 € 12.187 € 355 € 104
alemtuzumab € 29.301 € 28.432 € 859 € 10
Costo sanitario diretto pazienti afferenti al Centro SM di Cefalù – anno 2015
Farmaco Medicinale Costo sanitario
n°pazienti
Costo sanitario diretto
II linea natalizumab € 23.476 117 € 2.746.692fingolimod € 21.004 67 € 1.407.268
I linea
IFN beta 1A (Rebif 44) € 14.248 154 € 2.194.192IFN beta 1A (Rebif 22) € 10.706 48 € 513.888glatiramer acetato € 9.950 136 € 1.353.200IFN beta 1A (Avonex) € 10.291 39 € 401.349IFN beta 1b (Betaferon) € 6.327 18 € 113.886IFN beta 1B (Extavia) € 6.327 1 € 6.327teriflunomide € 10.406 0 € 0dimetil fumarato € 12.646 0 € 0
alemtuzumab € 29.301 0 € 0
€ 8.736.802
Attuale visione economica di un Centro SM
LUIGI
Direttore Generale
Farmacista
Neurologo
Risparmio SSR Sicilia per pazienti in sperimentazioni farmacologiche
(2014)
PAZIENTI IN SPERIMENTAZIONE (Cefalù)
Spesa SSR Nr. pazienti Totale Risparmio annuo per la Regione
€ €
Visite ambulatoriali (x 6) 13.5 200 16.200
Esami diagnostici (RMN, ematochimica, etc) 700 200 140.000
Terapie immunomodulanti 11.000 200 2.200.000
Sperimentazioni nei 17 Centri SM Regione Siciliana
Spesa SSR Nr. pazienti Totale Risparmio annuo per la Regione
€ €
Visite ambulatoriali (x4) 13.5 400 21.600
Esami diagnostici (RMN, ematochimica, etc) 700 400 280.000
Terapie immunomodulanti 11.000 400 4.400.000
Sistemaimmunitario BEE SNC
B
T
APC
IL-4IL-6
B*
M
riattivazione& espansione
TH1
TH 2
IL-10TGF-
-
Abs Abs
Kieseier e Wiendl, 2007
La SM è una malattia immunomediata cronica
Perché è così importante trattare il più precocemente ed efficacemente possibile?
Leray E. et al. Brain. 2010 Jul;133(Pt 7):1900-13.
Impossibile v isualizzare l'immagine.
00
Anni dall’inizio clinico della SM
EDSS
5 10 15 20 25 30
1
2
3
4
5
6
7
Fase I«Finestra terapeutica» per riuscire a modificare significativamente la progressione di malattia
9
Fase II
Presente e “futuro prossimo” delle DMT per la SM
FINGOLpo qd
DMFpo
CLADpo
DACLsq
LAQpo
GASq iw
?
PEG IFNsc
TERIFpo
ALZiv
GASq tiw
11
La terapia ottimale per la SM RR: un buon bilancio tra efficacia e problematiche
Meno efficace,con molte problematiche
Più efficace,con molte problematiche
Più efficace,con poche problematiche
Meno efficace,con poche problematiche
Efficacia:
Problematiche:
Ricadute DisabilitàAttività RMNAtrofia RMN
TolerabilitàSafetyCostiMonitoraggio
12
DMSC
Per Soelberg Sorensen
Efficacy of First‐ and second‐line drugs on annualized relapse rate
*Results (intent to treat) from separate clinical studies cannot be directly compared; †for patients completing 2 years in the study.
Relapse rate re
duction vs placebo
(%)
27%
34%29%
68%
32% 32%†
0
10
20
30
40
50
60
70
Dimethyl fumarate
SC IFNβ 1a tiw44 μg 22 μg
IM IFNβ 1aGlatiramer acetate
Natalizumab IFNβ 1b
P=0.0001P=0.002†
P<0.001
P=0.007P<0.005
P<0.001
Mitoxantron
55%P<0.001 53%
P<0.001
Fingolimod
44%48%P<0.001
P<0.001
22%
32%
66%
18%P=0.04
LaquinimodTeriflunomide
P=0.001
P=0.002
Data from Pivotal Placebo‐Controlled Studies
P<0.001
33%P<0.005
DF CF TEMSO TOWERSFRDS FRDS 2
FRDS: FREEDOMS; DF: DEFINE; CF: CONFIRM;
Effetti comparativi terapie SM
Efficacia
Problematiche (effetti indesiderati, costo, safety, etc.)
IFNβGA
14
La terapia ottimale per la SM RR: effetto sul tasso di ricaduta
Alemtuzumab
Fingolimod
Dimethyl‐fumarate
Mitox‐antrone
Teriflunomide
NatalizumabJCV Ab‐ JCV Ab+
Percorso paziente con SM recidivante remittente (SMRR)
SM Materiale di stimolo
Provenienza
Approvvig./
Aderenza
Mantenimentoe modifichedelle terapia
Sceltaterapeutica
Valutazione e Diagnosi
Consulto specialistico (e.g., urologo, fisioterapista, psicologo).
Inizio della terapia
Diagnosi di Sindrome Clinicamente Isolata (CIS)
I linea: interferone, Copaxone, TecfideraII linea: Tysabri, Gylenia
AvonexCopaxoneRebifBetaseron
Secondo episodio acuto
• Il paziente è compliante
• Paziente non compliante/interrom
pe/switch
Il paziente manifesta sintomi: problemi alla vescica/intestinali, depressione, astenia, dolore, spasticità, problemi
motori
Tempo medio impiegato per raggiungere un punteggio pari a 4 sulla scala EDSS: 8.1 anni
Ricerca di informazioni condotta autonomamente dal
pazienteIl paziente ignora i sintomi
Il neurologo monitora la progressione della malattia
Il paziente consulta il MMG/Oculista/Neurologo
Il paziente viene inviato al neurologo
Il neurologo effettua le analisi di routine
Diagnosi di SMRR
•Anamnesi/Rachicentesi/RM/Potenziali evocati visivi/EDSS
Il paziente manifesta i sintomi tipici (problemi alla vista/motorie,
sensazione di bruciore agli arti).
Primo episodio acuto/ingravescenza dei sintomi
Il paziente si reca in PS
• Risonanza Magnetica •EDSS
Percorso paziente con SM secondaria progressiva (SMSP)
Provenienza
Approvvig./
Aderenza
Mantenimento e modifiche delle terapia
Sceltaterapeutica
Valutazione e Diagnosi
Diagnosi pregressa di SMRR e trattemento con:I linea: interferone, CopaxoneII linea: Tysabri, Gylenia
Il neurologo monitora e traccia la progressione della malattia
RM e punteggi EDSS
Tempo medio impiegato per raggiungere un punteggio pari a 4 sulla scala EDSS: 8.1 anni
Diagnosi di SMSP
• Ingravescenza dei sintomi/declino neurologico
Consulto specialistico (e.g., urologo, fisioterapista, psicologo).
Non vi sono terapie approvate per la SMSP/il paziente non viene trattato
• Il paziente ècompliante con la
terapia sintomatica
•Il paziente non è compliante/interrompe/passa ad altra
terapia
Il paziente manifesta sintomi: problemi alla vescica/intestinali,
depressione, astenia, dolore, spasticità, problemi motori
Ridotta
frequenzadelle
recidiveTem
po medio
allaSM
SP: 12 anni
Impiego off label farmaci sintomatici: ciclofosfammide, metotrexato.
Il neurologo monitora la progressione della malattia
•RM•Punteggi EDSS
Percorso paziente con SM Primaria Progressiva (SMPP)
Provenienza
Valutazione e Diagnosi
Ricerca di informazioni condotta autonomamente dal
pazienteIgnora i sintomi
Il paziente consulta il MMG/Oculista/Neurologo
Il paziente viene inviato al neurologo
Il neurologo effettua le analisi di routine
Diagnosi di SMPP
•Anamnesi/Rachicentesi/RM/Potenziali evocati visivi/punteggio
EDSS
Il paziente manifesta i sintomi tipici (problemi alla vista/motorie,
sensazione di bruciore agli arti).
Primo episodio acuto/ingravescenza dei sintomi
Il paziente si reca in PS
Approvvig./ Aderenza
Mantenimento e modifiche delle terapia
Sceltaterapeutica
Il neurologo monitora la progressione della malattia
• Risonanza Magnetica •Punteggi EDSS
Consulto specialistico (e.g., urologo, fisioterapista, psicologo).
Non vi sono terapie approvate per la SMPP/il paziente non viene trattato
• Il paziente ècompliante con la
terapia sintomatica
•Il paziente non è compliante/interrompe/passa ad altra
terapia
Il paziente manifesta sintomi: problemi alla vescica/intestinali,
depressione, astenia, dolore, spasticità, problemi motori.
Tempo medio impiegato per raggiungere un
punteggio pari a 8 sulla scala EDSS: 18 anni.
Impiego di farmaci sintomatici: metilprednisolone, cladribina, metotrexato,
mitoxantrone.
Nuovi paradigmi assistenziali nell’ambito della SM
Players Punti chiave
Paziente / rete • Diagnosi precoce (incluso assetto cognitivo)
• Definizione tipologia del paziente (età, sesso, gravità, compliance, genetica)
• Trattamento precoce
• Algoritmi terapeutici “sequenziali”
• Impatto economico
• Follow up stringente all’inizio per rapidi switch (obiettivo: NEDA)• Risonanza Magnetica (carico lesionale, attività, atrofia)• Biomarcatori• Valutazione EDSS• Test cognitivi • Compliance
• Post-marketing (registri, farmacovigilanza)
Medico / infermiere
Istituzioni / Pharma
Traditional Therapies for RRMS Have Generalized Effects on the Immune System
• Enhancement of suppressor T-cell activity• Reduction of pro-inflammatory cytokine
production• Down-regulation of antigen presentation• Inhibition of lymphocyte trafficking to the
CNS• It is not known if these effects play an important
role in the observed clinical activity of IFNB-1b in MS
Proposed effects of IFNB-1b1
Proposed effects of glatiramer acetate2
• Modulation of immune processes believed to be responsible for MS pathogenesis
• Potential activation of suppressor T cells in the periphery (based on animal and in vitro systems)
• The mechanisms by which GA exerts its effects in patients with MS are not fully understood
Exact mechanisms of action have not been fully elucidated
BBB
Periphery
B
Mϕ
T
IFN-γTNF-α
Mϕ
IFN-γTNF-α
T
B
IL-10TNF-β
Treg
Interferon-beta
Glatiramer acetate
CNS
TT
T
Th2
APC
Clinical Efficacy and Safety of Peginterferon Beta-1a in Relapsing Multiple Sclerosis: Data from the Pivotal Phase 3 ADVANCE StudyProf Peter A. Calabresi, MDMarch 20, 2013
Peter A. Calabresi1, Bernd Kieseier2, Douglas L Arnold3, Laura Balcer4, Jean Pelletier5, Shifang Liu6, Ying Zhu6, Ali Seddighzadeh6, Bjorn Sperling6, Serena Hung6, Aaron Deykin6
1Johns Hopkins University, Baltimore, MD, USA; 2Heinrich-Heine University, Düsseldorf, Germany; 3Montreal Neurological Institute, McGill University, and NeuroRx Research, Montreal, Quebec, Canada; 4Department of Neurology, New York University, Langone Medical Center, New York, NY, USA; 5Departments of Neurology and Research (CRMBM), CHU Timone, Marseille, France; 6Biogen Idec Inc., Cambridge, MA, USA.
American Academy of Neurology65th Annual MeetingSan Diego, California
(n=500)(n=500) (n=512)
36% reductionP=0.0007
*Based on negative binomial regression; adjusted for baseline EDSS score (<4, ≥4), baseline relapse rate, age (<40 years, ≥40 years).Calabresi PA et al. ECTRIMS 2013.
Adj
uste
d A
nnua
lized
Rel
apse
Rat
e*
28% reductionP=0.0114
Phase 3 ADVANCE: Primary EndpointAnnualized Relapse Rate
Newer Agents (Approved and in Development)Have Specific Targets
BBB
Periphery
T
DC(APC)
B
Mϕ
T
IFN-γTNF-α
Mϕ
IFN-γTNF-α
T
B
IL-10TNF-β
Natalizumab6
Daclizumab7,8
OcrelizumabOfatumumab4
Fingolimod1
Lymph node
CNS
NKreg
T
Exact mechanisms of action have not been
fully elucidated
Approved
In Development
Remyelination
Anti-LINGO-19
SiponimodPonesimodRPC10632
MT13033
Laquinimod5
Alemtuzumab11
Teriflunomide10
Teriflunomide
DHO‐DH
A selective dihydro‐orotatedehydrogenase inhibitor
Blocks de novo pyrimidine synthesis, thus reducing the proliferation of autoreactive T‐and B‐cells
Preserves replication and function of cells (e.g. haemopoietic cells, memory T‐cells) living on the existing pyrimidine pool (salvage pathway)
Administered orally as 14 mg tablet once daily
DHO‐DH, dihydro‐orotate dehydrogenase
Blasting lymphocyte
De novo pathway
Pyrimidine pools Salvagepathway
CTP‐, UTP‐sugars Nucleotides CDP lipids
Glycoproteins, Glycolipids RNA, DNA Phospholipids
Cell‐cell contactAdhesion anddiapedesis
ProliferationIg secretion
Cell membranesSecond messengers
Non‐lymphoid
cells
Resting lymphocyte
Teriflunomide
Teriflunomide: efficacia terapeutica
TEMSOAnnualized Relaps Rate 3‐month Confirmed Progression
TENERE: Time to Failure
Teriflunomide: profilo di safety (TEMSO)
Patients (%) Placebo (n=360)
Teriflunomide 7 mg (n=368)
Teriflunomide 14 mg (n=358)
Nasopharyngitis 27.2 25.5 26.0
Headache 17.8 22.0 18.7
Diarrhoea 8.9 14.7 17.9
Fatigue 14.2 12.8 14.5
ALT increased 6.7 12.0 14.2
Nausea 7.2 9.0 13.7
Hair thinning 3.3 10.3 13.1
Influenza 10.0 9.2 12.0
Back pain 13.1 10.6 11.5
Urinary tract infection 9.7 7.3 10.3
Pain in extremity 13.1 7.1 9.2
Teriflunomide is teratogenic and pregnancy is contraindicated in 2 years after discontinuation of teriflunomide, unless treatment with cholestyramine or active charcoal is undertaken.
Teriflunomide: valutazione rischi / benefici
Noti disagi e possibili rischi Eventi avversi
Diarrea e nausea Alopecia ALT increase
Potenziali proprietàimmunosoppressive
Benefici accertati Effetto moderato sull’ARR Effetto moderato sulla progressione
di disabilità Equivalente a IFN‐β 1a SC Una sola pillola al giorno
Dimetilfumarato (BG 12)
Dimethyl Fumarate(DMF)
• Fumarate is a naturally occurring molecule that is essential for cellular oxidative respiration (Citric Acid Cycle)
• Dimethyl fumarate (DMF) 120 mg formulated into enteric‐coated oral microtablets contained in a capsule
• Administration: 240 mg twice daily
• DMF is rapidly and quantitatively converted to monomethyl fumarate (MMF) after absorption
Monomethyl Fumarate(MMF)
Dimetilfumarato: efficacia terapeutica (DEFINE)
Annualized relapse rate
Confirmed (3 months) disability progression
44%reductionvs. placeboP<0.0001
51%reductionvs. placeboP<0.0001
*ARR calculated with negative binomial regression, adjusted for baseline EDSS score (≤2.0 vs >2.0), baseline age (<40 vs ≥40 years), region, and number of relapses in the year prior to study entry.
29%reductionvs. placeboP=0.0128
ARR (95%
CI)*
Dimetilfumarato: efficacia terapeutica (CONFIRM)Annualized relapse rate
NS
Profilo di safety del Dimetilfumerato
Adverse Events Safety ResultsAEs with 5% difference in incidence BG-12 Group vs. placebo
47% vs 9% Flushing
9% vs 3% Upper Abdominal Pain
6% vs 0% Hot Flush
5% vs 0% Severe upper Abdominal Pain
5% vs 0% Paraesthesia
Discontinuations: 13% vs 9% (BG-12 vs placebo)
MS relapse was only SAE occurring in >1 pt/group. All others: PID, phlebitis, abdominal pain, urinary retention, MS only occurred in a single patient (N=192)
• Overall rate of Infection not different than Placebo (34%)
• Nasopharyngitis was the most common infectious AE, more in placebo
• No opportunistic infections reported
Kappos L et al. Lancet 2008; 372:1463–72
Few cases of PML in MS or psoriasis patients treated with dimethyl fumarate as monotherapy. Associated with low lymphocyte counts.
Dimetilfumarato: valutazione rischi / benefici
Noti disagi e possibili rischi Effetti avversi
Flushing Dolori abdominali
Due pillole al giorno Basso rischio di PML Benefici accertati
Buon effetto sull’attività di malattia Moderato effetto sulla
progressione della disabilità Numericamente ma non
statisticamente meglio del GA
Alemtuzumab overview
> INDICAZIONE TERAPEUTICA: indicato per i pazienti adulti con sclerosi multipla recidivante‐remittente (SMRR)con malattia attiva definita clinicamente o attraverso le immagini di risonanza magnetica1
> TIPOLOGIA: anticorpo monoclonale umanizzato prodotto mediante DNA ricombinante1
> TARGET: glicoproteina CD52 di superficie presente ad alte concentrazioni sui linfociti B e T1
> VIA DI SOMMINISTRAZIONE: infusione endovenosa1
> FREQUENZA DI SOMMINISTRAZIONE: 2 cicli a distanza di 12 mesi1
> POSOLOGIA: I ciclo: 12 mg/die per 5 giorni consecutivi (dose totale di 60 mg)1
II ciclo: 12 mg/die per 3 giorni consecutivi (dose totale di 36 mg)1
Alemtuzumab significantly reduced ARR and SADa vs IFNB-1a SC in treatment naïve patients at year 2
aIn the CARE-MS I study, there was no statistical significant in 6 month reduction of SAD.ARR, annualized relapse rate; HR, hazard ratio; SAD, sustained accumulation of disability.Kieseier BC et al. Presented at: American Academy of Neurology; 2014; Philadelphia. P2.209.
AR
R
0.36
0.15
56.4% reductionvs. SC IFNB-1a
P<0.0001
SC IFNB-1a 44 µgn=294
LEMTRADA 12 mgn=483
0.5
0.4
0.3
0.2
0.1
0.0
Pooled CAMMS223/CARE-MS I data
No. of Patients
SC IFNB-1a 44 µgLEMTRADA 12 mg
294 273 263 238 217483 478 465 450 433
292 261 243 230482 472 456 443
0
5
10
15
20
Patie
nts
with
6-M
onth
SA
D (%
)
0 6 12 183 9 15 21 24
13.9%
7.1%
Month
SC IFNB-1a 44 µg
LEMTRADA 12 mgHR: 0.50P=0.0029
50% reduction beyond that with SC IFNB-1a
ARR: Years 0–2 Time to 6-month SAD*
50
6862 60 62
40
0
20
40
60
80
100
Year 1 Year 2 Year 3 Year 4 Year 5 Year 3–5 (M24–60)
Prop
ortio
n of
Patie
nts, % (9
5% CI)
Proportion of Patients With NEDA Over 5 Years
• 40% of alemtuzumab patients achieved sustained NEDA over the 3 year extension study
Proportion Achieving NEDA was Maintained Over 5 YearsECTRIMS 2015
68% of patients received no alemtuzumab retreatment
since Month 12
369 326 324 319354No. of Patients 301
1. Arnold DL, Traboulsee A, Cohen JA, et al. Presented at: ECTRIMS; October 7-10, 2015; Barcelona, Spain, P1100.
Year 3‒5(Month 24‒60)
34
Core Study Extension Study
Sustained NEDA
Clinical diseaseactivity-free 82% 85% 82% 84% 85% 65%
MRI activity-free1 60% 77% 72% 70% 70% 54%
Risks identified during the ALEMTUZUMAB clinical development programIdentified Risk Rate in LEMTRADA‐
Treated Patients Notes
ITP
~1% (1 fatality prior to implementation of monitoring program)1
• Onset generally occurred 14‐36 mo after first exposure1
• Most cases responded to first‐line medical therapy1
Nephropathies0.3%
(anti‐GBM n=2)1
• Generally occurred within 39 mo after last administration1
• Responded to timely medical treatment and did not develop permanent kidney failure2
Thyroid disorders(Hypo‐/hyper‐)
~36%a
(serious, 1%)1
• Onset occurred 6‐61 mo after first LEMTRADA exposure; peaked in year 3 and declined thereafter3
• Most mild to moderate, most managed with conventional medical therapy, however, some patients required surgical intervention1
• Higher incidence in patients with history of thyroid disorders1
IARs>90%
(serious, 3%)4,5
• Occurred within 24 h of LEMTRADA administration1
• Most mild to moderate; rarely led to treatment discontinuation1
• May be caused by cytokine release following mAb‐mediated cell lysis1
Infections71%
(serious, 2.7%)1
• Incidence highest during first mo after infusion; rate decreased over time3
• More common with LEMTRADA; predominately mild to moderate in severity1
• Generally of typical duration; resolved following conventional medical treatment1
Aut
oim
mun
e Ev
ents
aThrough 48 mo after first exposure. ITP, immune thrombocytopenia; GBM, glomerular basement membrane; mAb, monoclonal antibody.1. LEMTRADA Summary of Product Characteristics. Genzyme Therapeutics Ltd, UK; September 2013; 2. Wynn D, et al. Presented at: European Committee for Treatment and Research in Multiple Sclerosis; 2013; Copenhagen; P597; 3. Coles AJ, et al. Neurology. 2012;78:1069-1078; 4. Coles AJ, et al. Lancet; 2012;380:1829-1839; 5. Cohen JA, et al. Lancet. 2012;380:1819-1828.
Efficacy and Safety of Ocrelizumab in Relapsing Multiple Sclerosis – Results of the Phase III Double-blind,
Interferon beta-1a-controlled OPERA I and II Studies
SL Hauser, GC Comi, H-P Hartung, K Selmaj, A Traboulsee, A Bar-Or, DL Arnold, G Klingelschmitt, F Lublin, H Garren, L Kappos,
on behalf of the OPERA I and II clinical investigators
OPERA I, NCT01247324; OPERA II, NCT01412333
31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis 2015
Platform presentation number 190
Primary endpoint:Significant reduction in ARR compared with IFN β-1a
ITT*Adjusted ARR calculated by negative binomial regression and adjusted for baseline EDSS score (<4.0 vs ≥4.0), and geographic region (US vs ROW).ARR, annualised relapse rate; EDSS, Expanded Disability Status Scale; IFN, interferon; ROW, rest of the world.
0,292
0,156
0,0
0,1
0,2
0,3
0,4
0,5
IFN β-1a 44 μg
(n=411)
Ocrelizumab 600 mg(n=410)
Adj
uste
d A
RR a
t 96
Wee
ks*
0,290
0,155
0,0
0,1
0,2
0,3
0,4
0,5
IFN β-1a 44 μg
(n=418)
Ocrelizumab 600 mg(n=417)
Adj
uste
d A
RR a
t 96
Wee
ks*
46% ARR reduction
vs IFN β-1ap<0.0001
OPERA I OPERA II
47%ARR reduction
vs IFN β-1ap<0.0001
Secondary endpoint: Significant reduction in number of T1 Gd+ lesions compared with IFN β-1a
0,286
0,0160,0
0,1
0,2
0,3
0,4
0,5
IFN β-1a 44 μg
(n=411)
Ocrelizumab 600 mg(n=410)
Mea
n N
umbe
r of T
1 G
d-en
hanc
ing
Lesio
ns p
er M
RI S
can*
0,416
0,0210,0
0,1
0,2
0,3
0,4
0,5
IFN β-1a 44 μg
(n=418)
Ocrelizumab 600 mg(n=417)
Mea
n N
umbe
r of T
1 G
d-en
hanc
ing
Lesio
ns p
er M
RI S
can*
OPERA I OPERA II
94%Reduction vs
IFN β-1ap<0.0001
95%Reduction vs
IFN β-1ap<0.0001
ITT*Adjusted by means calculated by negative binomial regression and adjusted for baseline T1 Gd lesion (present or not), baseline EDSS (<4.0 vs ≥4.0) and geographical region (US vs ROW).EDSS, Expanded Disability Status Scale; Gd+, gadolinium enhancing; IFN, interferon; MRI, magnetic resonance imaging; ROW, rest of the world.
Efficacy and Safety of Ocrelizumab in Primary Progressive Multiple Sclerosis – Results of the
Phase III, Double-blind, Placebo-controlledORATORIO Study
X Montalban, B Hemmer, K Rammohan, G Giovannoni, J de Seze, A Bar-Or, DL Arnold, A Sauter, D Masterman, P Chin, H Garren, J Wolinsky,
on behalf of the ORATORIO clinical investigators
NCT01194570
31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis 2015
Platform presentation number 228
Secondary endpoint: Significant reduction in 24-week CDP
n
Placebo 244 234 214 202 193 183 176 166 157 148 139 125 89 70 50 33 22 7 2Ocrelizumab 487 465 454 437 421 397 384 367 349 330 313 290 217 177 144 87 50 21 7
Analysis based on ITT population; p-value based on log-rank test stratified by geographic region and age.Patients with initial disability progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression.CDP, confirmed disability progression; EDSS, Expanded Disability Status Scale; HR, hazard ratio; ITT, intent to treat.
Time to 24-week Confirmed Disability Progression
25% reduction in risk of CDP
HR (95% CI): 0.75 (0.58, 0.98); p=0.0365
Secondary endpoint: Significant reduction in the rate of whole brain volume loss
nPlacebo 203 200 150Ocrelizumab 407 403 325
17.5% reduction vs placebo
p=0.0206*
Percent Change of Whole Brain Volume from Week 24 to Week 120
*Analysis based on ITT population with week 24 and at least one post-week 24 assessment; p-value based on MMRM at 120 week visit adjusted for week 24 brain volume, geographic region and age.CI, confidence interval; ITT, intent to treat.
-1.1%
-0.90%
L’approccio tradizionale al trattamento della SM
•Il decorso di malattia è molto eterogeneo tra I vari pazienti….e ciò nel tempo condiziona le scelte terapeutiche1-3
421. Rio J et al. Ann Neurol 2006;59:344-52; 2. Miller A et al. J Neurol Sci 2008;274:68-75; 3. Rudick RA et al. Lancet Neurol 2009;8:545-59. Figure adapted from Rio J et al. Curr Opin Neurol 2011; 24:230-7.
A
B
C
D
E
YX
Moderataefficacia
Alta o molto altaefficacia
TrattamentoInizialeTerapie
di 1° lineaTerapie di 2° linea
Interferoni, Glatiramer Acetate,BG-12, Teriflunomide, Fingolimod
(Daclizumab, Laquinimod)
Natalizumab, Alemtuzumab(Mitoxantrone, Ciclofosfamide)
Terapie Combinate ?
ASCT
Induzionevs
Escalationvs
Sequenziale
Terapia della SM(2015 “standard”)
?
Interferoni, GA, BG-12, Teriflunomide, Fingolimod, Natalizumab, Alemtuzumab
(Daclizumab, Laquinimod)
Mitoxantrone, Ciclofosfamide
Terapie Combinate ?
ASCT
Terapia della SM(2015 “ideale”)
Induzionevs
Escalationvs
Sequential
Potenziale sequenza di inizio trattamento in pazienticon CIS o early active RR MS (2015)
Interferon‐beta (1b and 1a) o Glatiramer acetato
Teriflunomide (specie maschi)
Dimetilfumarato
NatalizumabAlemtuzumab
1
7
3
4
65
Fingolimod
2Interferon‐beta (1b and 1a)
bFGF/EGF
Shh
PDGF/bFGF
Neural Stem Cell Oligodendrocyte Progenitor
PremyelinatingOligodendrocyte
PDGF/bFGFGROα CNTF/T3
MS
Demyelinated axons
Remyelinated axons
Anti-LINGO-1 mAb
Anti-LINGO-1 AntagonistAntibodies Promote Remyelination
Adapted from Jackman N et al. Physiology. 2009;24:290-297; Zhang SC. Nat Rev Neurosci. 2001;2:840-843
Con
trol
RN
Ai
LIN
GO
-1 R
NA
i
P<0.001
No RNAi
Control RNAi
LINGO-1RNAi
0
5
10
15
20
25
Mat
ure
Olig
oden
droc
ytes
(%To
tal)
LINGO-1 Blockade Results in OligodendrocyteDifferentiation
RNAi=ribonucleic acid interference. Mi S et al. Nat Neurosci. 2005;8:745-751.
Anti-LINGO-1 is not approved for MS. BIIB
-GE
R-0
339
Cuprizone Model
Lysolecithin Model
ExperimentalAutoimmuneEncephalitis (EAE)
Anti-LINGO-1 Antibody Results in Remyelination in Animal Models of Demyelination
** *
**
Adapted from Mi S et al.Ann Neurol 2009;65:304-315.
*
**
*
Control Anti-LINGO-1
*Demyelinated Axons Remyelinated Axons
*
0
20
40
60
80
Mye
linat
edA
xon
s (%
)
*P<0.05
0
20
40
60
80
Mye
linat
edA
xon
s (%
)
*P<0.02
0
20
40
60
80
Mye
linat
edA
xon
s (%
)
*P<0.05
Anti-LINGO-1 is not approved for MS.
Anti-LINGO-1 Phase II Clinical Development Plan
q4wks=every 4 weeks; IM=intramuscular; IFNβ=interferon beta; EDSS=Expanded Disability Status Scale; T25FW=Timed 25-Foot Walking Test; 9HPT=9-Hole Peg Test; PASAT=Paced Auditory Serial Addition Test; MRI=magnetic resonance imaging; MTR=magnetization transfer ratio; DTI=diffusion tensor imaging.ClinicalTrials.gov Identifiers: RENEW: NCT01721161; SYNERGY: NCT01864148.
Acute Optic Neuritis
• Placebo-controlled proof of concept
• Subjects with recent first episode of acute optic neuritis
• Dose: 100 mg/kg q4wks ×6
• Endpoints: – Visual evoked potential (VEP)/multifocal
VEP (latency delay) – Optical coherence tomography (retinal
nerve fiber and ganglion cell layer loss)– Visual function (low contrast letter acuity,
visual quality of life)
Relapsing Forms of MS• Placebo-controlled proof of concept
and dose ranging • Subjects with RRMS and relapsing
SPMS receiving IM IFNβ-1a• Dose: 3, 10, 30, 100 mg/kg q4wks ×18
• Physical and cognitive endpoints:– EDSS/T25FW/9HPT/PASAT composite– Primary=improvement– Key secondary=delayed progression– MS-COG– MRI (MTR, DTI, black holes, atrophy)
BIIB033 (Anti-LINGO-1) is not approved for MS.
Perron et al . PlosOne2013
C57/Bl6 mouse EAE with MOG antigen
Env induces MS-like symptoms in mice
Env induces demyelination in mice
In vitro toxicity shown on different cells
MSRV‐Env appears as a critical target for MS pathogeny
PSSV presentation v1.0_17‐Aug‐2015_Final l Confidential51
Phase IIa study design and patient characteristics
PSSV presentation v1.0_17‐Aug‐2015_Final l Confidential52
Single-blind, placebo-controlled dose-escalatingrandomised study, followed by a 12 month open-label extension• IV administration of GNbAC1 every 4 weeks• 10 patients recruited in Basel and Geneva, allocated in 2
cohorts of 2 mg/kg and 6 mg/kg• Inclusion criteria: EDSS up to 6.5; exclusion of patients with
any other treatment; no MSRV-Env level requirements• 9 out of 10 patients had progressive MS
EDSS (mean)
RRMS (n=1)
2.5
PPMS (n=3)
5.0
SPMS (n=6)
5.2
Alemtuzumab
Daclizumab
Phase I Phase II Phase III Registration
Secukinumab
Ocrelizumab
Tabalumumab
Ofatumumab
GNbAC1
BIIB033
T & NK cells
MS specific factors
B cells
Targets
Pipeline of mAbs in MS clinicaldevelopment
PSSV presentation v1.0_17‐Aug‐2015_Final l Confidential53
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